INTRODUCTION

Congenital nephrotic syndrome (CNS) is defined as nephrot-ic syndrome which manifests in utero or during the first 3months of life (1). Although CNS may develop secondary tounderlying diseases such as various kinds of congenital infec-tions, most of CNS is primary lesion of genetic origin. Recentgenetic studies disclosed four major causative genes impli-cating CNS; the NPHS1 gene encoding nephrin, the NPHS2gene encoding podocin, the WT1 gene encoding the nucle-ar transcriptional factor Wilms tumor suppressor gene 1, andthe LAMB2 gene encoding laminin β2 chain (2).

CNS of Finnish type (CNF, OMIM #602716) is an auto-somal recessive disease due to NPHS1 mutations. CNF is themost common CNS in Finland with the incidence of 1 per10,000 births. However, patients with CNF have also beenreported worldwide. Most of the patients develop nephroticsyndrome at birth or soon after birth, which progresses rapid-ly to end-stage renal disease. Kidney transplantation is theonly curative treatment modality currently (3-5).

In Korea, only few cases with rather typical clinicopatho-logic findings of CNF have been reported (6, 7). However,

genetic study was done in none of those cases. Here we reportthe two infants with CNF which was confirmed by molecu-lar genetic study for the first time in our country.

CASE REPORTS

Case 1

A 2 months old male infant was admitted to a local hos-pital due to generalized edema. On prenatal examination,high α-fetoprotein (AFP) level (20.85 MoM) in the mater-nal serum was detected at the 18th gestational week. Thebaby was born at 36 weeks of gestational age with a birthweight of 2.57 kg. The weight of placenta was reported tobe normal. Apgar scores at 1 and 5 min were 9 and 10 points,respectively. However, he showed shortness of breath andabdominal distension soon after the birth. He has normalmale external genitalia. Laboratory tests revealed markedlyhypoalbuminemia (serum albumin 1.2 g/dL), massive pro-teinuria (urinary protein excretion 7,959 mg/m2/day), andhypothyroidism. There was no evidence of congenital infec-

S210

Beom Hee Lee*, Yo Han Ahn*, Hyun Jin Choi*, Hee Kyung Kang*, Sung-Do Kim�, Byoung-Soo Cho�, Kyung Chul Moon�,�, Il Soo Ha*,�, Hae Il Cheong*,�, and Yong Choi*,�

Department of Pediatrics*, Seoul National UniversityChildren’s Hospital, Seoul; East West Kidney DiseasesResearch Institute, Department of Pediatrics�, Kyung-Hee University Hospital, Seoul; Department of Pathology�, Seoul National University Hospital, Seoul;Kidney Research Institute, Medical Research Center�,Seoul National University College of Medicine, Seoul,Korea

Address for correspondenceHae Il Cheong, M.D.Department of Pediatrics, Seoul National UniversityChildren’s Hospital, 28 Yeongeon-dong, Jongno-gu,Seoul 110-744, KoreaTel : +82.2-2072-2810, Fax : +82.2-743-3455E-mail : cheonghi@snu.ac.kr

*This study was supported by a grant (06-2008-192-9)from Seoul National University Hospital.

J Korean Med Sci 2009; 24 (Suppl 1): S210-4ISSN 1011-8934DOI: 10.3346/jkms.2009.24.S1.S210

Copyright � The Korean Academyof Medical Sciences

Two Korean Infants with Genetically Confirmed Congenital NephroticSyndrome of Finnish Type

Congenital nephrotic syndrome is defined as nephrotic syndrome which manifestsin utero or during the first 3 months of life. The prototype of congenital nephroticsyndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716),which is caused by loss-of-function mutations of the nephrin gene (NPHS1). Therehave been few clinical case reports of CNF in Korea, but none of which was con-firmed by genetic study. Here, we report two children with congenital nephrotic syn-drome. Genetic analysis of the NPHS1 gene revealed compound heterozygousframe-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 andc.3250_3251insG causing p.V1084GfsX12) in one patient and a missense muta-tion (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G caus-ing p.Y814X) in the other patient. The nonsense mutation was novel. The clinicalcourses of the patients were typical of CNF. This is the first report of geneticallyconfirmed CNF in Korea to date. The early genetic diagnosis of CNF is importantfor proper clinical management of the patients and precise genetic counseling ofthe families.

Key Words : Congenital Nephrotic Syndrome; Congenital Nephrotic Syndrome of Finnish Type; NPHS1Gene; Nephrin; Mutation

Received : 27 May 2008Accepted : 29 July 2008

Infants with Congenital Nephrotic Syndrome of Finnish Type S211

tion. The parents and his older brother are all healthy exceptthat his mother is a hepatitis B virus antigen carrier. Capto-pril (0.1 mg/kg/day) and synthyroid (2.7 μg/kg/day) werestarted as well as intermittent albumin infusions. However,generalized edema was aggravated with frequent need ofalbumin infusion. At 2 months of age, he was transferred toSeoul National University Children’s Hospital because ofintractable generalized edema and respiratory difficulty. Onadmission, his body weight was 4.49 kg (3-10 percentile),and height was 52 cm (<3 percentile). He showed mild chestretraction, and breathing sound was coarse with crackles onboth lung fields. The serum albumin was 1.6 g/dL, serum

creatinine was 0.3 mg/dL, random urine protein/creatinineratio was 110 mg/mg, platelet count was 888×103/μL, andserum immunoglobulin G level was 64 mg/dL (normal range,176-201 mg/dL). The nasopharyngeal aspirate was positivefor human respiratory syncytial virus A. Thus, in additionto supportive lung care, intravenous immune globulin (0.5g/kg) was given. He was medicated with indomethacin (4mg/kg/day), captopril (4.7 mg/kg/day), dipyridamole (3 mg/kg/day), warfarin, and synthyroid as well as high protein (upto 4 mg/kg/day) and high calorie diet (120 Cal/kg/day). How-ever, frequent albumin infusion (2 g/kg/day) had to be con-tinued to control respiratory problem and generalized edema,

Fig. 1. Renal biopsy findings of both patients (A, Case 1; B, Case 2). The glomeruli showed mesangial hypercellularity in both cases, anddiffuse increase of mesangial matrix was noted in Case 2. Tubules revealed focal mild atrophy or loss with focal moderate infiltration ofmononuclear cells and mild fibrosis in interstitium in both patients (PAS staining. Magnification: ×400).

A B

Fig. 2. Electron microscopic findings of the glomerulus in both cases (A, Case 1; B, Case 2). While the glomerular basement membrane(GBM) measured normal in average thickness with relatively smooth inner and outer contours in Case 1, diffuse thinning of GBM (100 μm)was noted in Case 2. No electron-dense deposits were found. Epithelial foot processes exhibited wide effacement (Magnification: ×7,000[A], ×10,000 [B]).

A B

S212 B.H. Lee, Y.H. Ahn, H.J. Choi, et al.

and a Chemoport� was implanted into right atrium via rightexternal jugular vein to secure a central venous line. An openrenal biopsy was performed at 4 months of age, which showeddiffuse mesangial proliferation (Fig. 1A, 2A). Genetic anal-ysis of the NPHS1 gene revealed compound heterozygousframe-shifting mutations, 8-bp deletion in exon 16 (c.2156_2163 delTGCACTGC causing p.L719DfsX4), and 1-bpinsertion in exon 24 (c.3250_3251insG causing p.V1084-GfsX12) (Fig. 3A, B). The former mutation was inheritedfrom mother, and the latter from father. During follow-up,he was admitted 2 more times due to central line infections.Thus, at 8 months of age, Chemoport� removal and unilat-eral nephrectomy were done to control the recurrent infec-tions and to reduce the degree of proteinuria and the needof albumin infusions, respectively.

Case 2

A female newborn baby was admitted to neonatal inten-sive care unit of Kyung Hee University Medical Center dueto respiratory difficulty, which was detected at birth. Shewas born at 38 weeks of gestational age, and the birth weightwas 2,920 gm. Apgar scores at 1 and 5 min were 7 and 9points, respectively. There was no abnormality on routineprenatal examinations. She is the first baby of healthy par-ents. On physical examination, she showed tachypnea andgeneralized edema. The serum albumin was 1.5 g/dL, serumcreatinine was 0.3 mg/dL, random urine protein/creatinineratio was 64.4 mg/mg, platelet count was 377×103/μL, and

serum immunoglobulin G level was 146 mg/dL. She hasnormal female external genitalia. Captopril (1.5 mg/kg/day),dipyridamole and synthyroid were started as well as dailyintravenous albumin infusions (1 g/kg/day). A kidney biop-sy, which was done at 1 month of age, revealed diffuse mesan-gial proliferation (Fig. 1B, 2B). Genetic analysis of the NPHS1gene revealed compound heterozygote mutations, a missensemutation in exon 11 (c.1381G>A causing p.R460Q) inherit-ed from mother and a nonsense mutation in exon 18 (c.2442C>G causing p.Y814X) inherited from father (Fig. 3C, D). At1.5 months of age, she was discharged, and her family emi-grated to Japan.

DISCUSSION

The cardinal clinical manifestation of nephrotic syndromeis massive proteinuria due to impairments of the glomerularfiltration barrier, which is composed of 3 layers: the fenestrat-ed endothelium, the glomerular basement membrane, andthe podocyte foot processes with bridging slit diaphragms.Recent molecular genetic studies have identified several genesinvolved in the pathogenesis of hereditary nephrotic syn-dromes, and most of these genes encode proteins of the glo-merular podocyte or the glomerular basement membrane ornuclear transcription factors expressed in the podocytes (NP-HS1, NPHS2, CD2AP, ACTN4, TRPC6, PLCE1, LAMB2,WT1, etc).

The onset of nephrotic syndromes associated with genetic

Fig. 3. Results of the NPHS1 gene analysis of both patients. Case 1 has two frame-shifting deletions, c.2155_2162 delCTGCACTG in exon16 (A) and c.3250_3251insG in exon 24 (B). The former was inherited from mother, and the latter from father (data not shown). Case 2 hasc.1381G>A mutation in exon 11 in one allele (C) and c.2242C>G in exon 18 in the other allele (D). The former was inherited from mother,and the latter from father (data not shown).

A

delCTGCACTG

370360350

C T A T C A G C C G C A C C G C T G A A G C T

B

delG

150140

T C G G G G G G G T C C C C C G G G A A

C

3′>5′complementary sequencesC>T

180170

C A G C C T C A C C T G G G T C C C A G C

D

C>G

190180

T G G C G C T T A C C A G T G C A T T G

Infants with Congenital Nephrotic Syndrome of Finnish Type S213

defects differs from each other. The NPHS1 gene, whichencodes nephrin, a major component of the slit diaphragm,is the first gene identified to be associated with hereditarynephrotic syndrome, CNF (3). Mutations in NPHS1 are exclu-sively detected in patients with CNS (3). Podocin, which isencoded by the NPHS2 gene, is another essential componentof the slit diaphragm and a close interactor of nephrin. Genet-ic defect of podocin is the cause of early-onset autosomal reces-sive steroid-resistant nephrotic syndrome (OMIM #600995)(8). The WT1 gene functions both as a tumor suppressor anda critical regulator of kidney and gonad development. Ger-mline mutations in WT1 result in two clinical syndromeswith glomerular diseases, Denys-Drash syndrome (OMIM#194080) and Frasier syndrome (OMIM #136680), as wellas isolated steroid-resistant nephrotic syndrome (9, 10). TheLAMB2 gene encodes laminin-β2 chain, which is one of themajor components of the glomerular basement membrane.Mutations in LAMB2 present with a spectrum of clinicalphenotypes from isolated early onset nephrotic syndrome tothe full syndromic phenotype of Pierson syndrome with CNS,diffuse mesangial sclerosis, microcoria, and mental retarda-tion (OMIM #609049) (11-13). Mutations in PLCE1, whichis also called as NPHS3 and encodes phospholipase C epsilon,can cause autosomal recessive early onset nephrotic syndromewith rapid progression to end-stage renal disease (14). Muta-tions of the ACTN4 (encoding α-actinin-4), TRPC6 (encod-ing canonical transient receptor potential 6 ion channel) andCD2AP (encoding CD2-associated protein) genes are primar-ily associated with autosomal dominant focal segmentalglomerulosclerosis in adults (15-17).

A recent genetic study of a large number of European andTurkish children with CNS disclosed that 84.8% of patientswith CNS (39 of 46 families) carried disease-causing muta-tions in one of the four genes; 18 (39.1%) in NPHS1, 18 (39.1%) in NPHS2, 1 (2.2%) in WT1, and 2 (4.4%) in LAMB2(2). In our country, the incidence of WT1 mutations in chil-dren with steroid-resistant nephrotic syndrome is similar tothose of other countries (18), and cases with LAMB2 muta-tions have also been reported (13). In contrast, NPHS2 muta-tions appear to be very uncommon in Korea as same as inother Far East Asian countries (China and Japan) (18). How-ever, there has been no genetic study of CNS with NPHS1mutations before this paper in Korea.

Precise diagnosis of CNF can be confirmed only by genet-ic analysis of NPHS1. To date, about 100 different mutationshave been identified in the NPHS1 gene. Two founder muta-tions, Finmajor (c.121delCT causing p.L41fsX90) and Finminor

(p.R1109X), account for nearly 90% all affected Finnishpatients (4, 5). On the other hand, most patients outsideFinland have individual mutations of different types (2, 4,14, 19). Among the four mutations detected in this study,one nonsense mutation (p.Y814X) is novel, and other threeare known mutation (3, 20).

Compared with many other genetic disorders, NPHS1

shows relatively little phenotypic variation (21). Most of thepatients with CNF are born prematurely with abnormallyenlarged placenta (the placental weight is over 25% of thenewborn weight). Proteinuria begins in utero and and full-blown nephrotic syndrome follows soon after birth. The clini-cal courses are commonly complicated by poor nutritionalstatus, growth delay, recurrent infections, thromboembolism,and hypothyroidism, and progression to end-stage renal dis-ease within 3-8 yr of life is inevitable (5).

Renal biopsy does not reveal the etiology of CNS, becausethe pathologic findings overlap in different genetic entities.The most characteristic renal pathologic findings of CNFare expansion of glomerular mesangium and dilations of theproximal and distal tubules. Effacement of podocyte foot pro-cesses and disappearance of the filamentous image of podocyteslit diaphragm are seen in electron microscopy, althoughnone of these findings are pathognomonic for CNF (5, 21).However, immunohistochemistry for nephrin expression ina biopsy sample is useful.

Steroids or other immunosuppressive drugs are not effectiveat all in all forms of hereditary proteinuric diseases includingCNF, although rare exceptional cases have been reported (14).Thus, successful kidney transplantation is the only curativetreatment. During infantile period with active nephrotic syn-drome, several conservative managements are recommendedto control severe edema such as daily or every other day albu-min infusion with intermittent gamma globulin replacement,and low-salt diet. A combination treatment of angiotensinconverting enzyme inhibitor and indomethacin lowers intra-glomerular pressure and, therefore, decreases urinary proteinexcretion. It is also important to prevent and treat infectiousand thrombotic complications. Optimal nutrition includ-ing vitamin and thyroid hormone should also be providedfor the patients to grow and develop as normally as possible.However, unilateral or bilateral nephrectomy and early dial-ysis before the development of renal failure may be requiredin some patients to control massive protein loss. When thepatient reaches a body weight of 8 to 9 kg, renal transplan-tation can be considered (1, 5).

Elevated AFP levels in amniotic fluid and maternal serum,which reflects fetal proteinuria in utero, can be used as a pre-natal diagnostic marker of CNF. However, because heterozy-gous fetal carriers of NPHS1 mutations may have temporar-ily elevated AFP levels, prenatal diagnosis should be basedon genetic testing whenever possible in high risk families.Otherwise, repeated measurement of amniotic fluid AFPbefore the 20th week of pregnancy is recommended (5). Incase of no family history or if the mutations in the affectedsibling(s) were not identified yet, prenatal diagnosis of CNFmay be based on high amniotic fluid AFP level only, becausewhole sequencing the NPHS1 (total 29 exons) gene is timeconsuming (5). Amniotic fluid AFP level can be elevatedfetal anencephaly or other malformations as well. ElevatedAFP levels in amniotic in maternal serum was detected in

S214 B.H. Lee, Y.H. Ahn, H.J. Choi, et al.

Case 1 of this study, but nevertheless the prenatal diagnosisof CNF was missed. It may be due to unfamiliarity of CNFto clinicians in our country.

In conclusion, this is the first report of Korean childrenwith CNF, which was confirmed by molecular genetic stud-ies. Precise genetic diagnosis is important for proper man-agement of the patients and accurate genetic counseling ofthe families. In addition to NPHS1, further molecular genet-ic study of NPHS2, WT1, and LAMB2 will provide moredetailed information about the genetic background in theKorean patients with CNS.

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